Innovative nanotechnology formulations for the treatment of yeast infections in oral mucosa
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2018
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La candidiasis oral es una infección provocada por hongos oportunistas que generalmente afecta a personas con inmunodeficiencia, bien por una infección viral o por un síndrome asociado a otras causas. Sin embargo, en algunos casos pueden verse afectadas personas sanas. Aunque Candida albicans es el principal agente patógeno causante de esta enfermedad, las infecciones por otras especies de Candida, como C. krusei, C. glabrata y C. dubliniensis también se han relacionado con la candidiasis oral. A pesar de los progresos en el tratamiento, polienos (como la nistatina) y azoles siguen siendo los agentes antifúngicos más utilizados para el tratamiento de estas infecciones. No obstante, la mayoría de estos agentes presentan algunas desventajas tales como la mala absorción oral del fármaco, el contenido en alcohol de las formulaciones y la necesidad de una administración muy frecuente.
Por lo tanto, el principal desafío en el tratamiento de las infecciones orales por Candida consiste en el aumento de la penetración y la permanencia de los antifúngicos en contacto con la mucosa oral o mucosa bucal. Para ello, la tecnología de la encapsulación constituye una posible estrategia. Así, el objetivo principal de esta Tesis ha sido el estudio de la encapsulación de agentes antifúngicos en varios tipos de partículas poliméricas con propiedades mucoadhesivas, incorporadas en formulaciones de aplicación bucal como pasta de dientes, gel oral y películas orales (sin alcohol) con la finalidad de aumentar su eficacia.
En este contexto, cabe destacar que tres de las formulaciones de nanopartículas evaluadas, nanopartículas de ácido poliláctico, de ácido poli(láctico-co-glicólico) y de alginato cargadas con nistatina, uno de los medicamentos antifúngicos más utilizados en el mercado, presentan ventajas por su tamaño de partícula, carga superficial y eficacia de encapsulación del fármaco. Cuando dichas nanopartículas se incorporan en una formulación semisólida se obtienen perfiles de liberación, permeabilidad, y mucoadhesión que aumentan la eficacia del tratamiento frente a una solución comercial de nistatina, sin detectarse toxicidad de los componentes de la formulación.
Asimismo, con la finalidad de convertir estas formulaciones en un tratamiento más natural, se determinó la actividad antifúngica de extractos de planta procedente de Glycyrrhiza glabra (regaliz). Una vez identificado el extracto con mayor actividad, y uno de los principales compuestos responsables de la misma, se procedió a su encapsulación
en los sistemas de nanopartículas anteriormente mencionados.
En conclusión, la formulación final desarrollada presenta un mejor perfil terapéutico en comparación con la solución comercial de nistatina, indicando que la encapsulación del fármaco antimicótico en asociación con un extracto natural podría constituir un futuro tratamiento con éxito.
Oral candidiasis is an opportunistic fungal infection that generally affects people with immunodeficiency due to viral infection or acquired immunodeficiency associated to other causes but in some rare cases, it can also affect healthy people. Despite the advances in the treatment of the oral candidiasis, polyens (like nystatin) and azoles are still the most used antifungal agents. In addition, most of those treatments present some disadvantages such as poor oral absorption of the drug, alcohol content in dosage form and they generally require a very high frequency of administrations. Therefore, the major challenge in the treatment may be focused on the improvement of the oral absorption of the antifungal agents through oral or buccal mucosa using bioadhesive dosage forms. This thesis aimed to develop a suitable buccal mucoadhesive nanoparticle (NP) formulation containing antifungal agents for the local treatment of oral candidiasis. Several types of polymeric particles with an encapsulated antifungal agent were prepared and further included into a toothpaste, an oral gel and oral films (all free of alcohol). Nystatin (Nys) was herein chosen as the reference drug because it is one of the main antifungal drug used. In this context, three different systems of nanoparticles (NPs), Polylactic acid, Poly(lactic-co-glycolic) acid and Alginate, were selected since they present a small particle size (300 to 800 nm), homogenous size distribution, appropriate surface charge, high encapsulation efficiency of Nys (above 70%), prolonged release profile, high adhesion capacity to oral mucosa, permeation capacity through the oral mucosa and safety profile. Also, the NPs successfully maintained the activity of Nys over time. Concerning the stability study the formulations were stable for 6 months. In addition, instead of Nys, extracts from Glycyrrhiza glabra (Licorice) were prepared and their antifungal activity was studied. The results obtained showed that ethanolic extract of Glycyrrhiza glabra L. was the most active extract and that the loaded NPs were successfully produced, presenting a mean size between 100-900 nm and a negative surface charge with high encapsulation efficiency of the extract. In conclusion, this thesis confirmed that all biodhesive nanoformulations using Nys or extracts from plants are viable alternatives for improving drug bioavailability in the oral mucosa. Thus, all nanoformulations might potentially improve the patient compliance due to its extended action and reduced the overall required dosage.
Oral candidiasis is an opportunistic fungal infection that generally affects people with immunodeficiency due to viral infection or acquired immunodeficiency associated to other causes but in some rare cases, it can also affect healthy people. Despite the advances in the treatment of the oral candidiasis, polyens (like nystatin) and azoles are still the most used antifungal agents. In addition, most of those treatments present some disadvantages such as poor oral absorption of the drug, alcohol content in dosage form and they generally require a very high frequency of administrations. Therefore, the major challenge in the treatment may be focused on the improvement of the oral absorption of the antifungal agents through oral or buccal mucosa using bioadhesive dosage forms. This thesis aimed to develop a suitable buccal mucoadhesive nanoparticle (NP) formulation containing antifungal agents for the local treatment of oral candidiasis. Several types of polymeric particles with an encapsulated antifungal agent were prepared and further included into a toothpaste, an oral gel and oral films (all free of alcohol). Nystatin (Nys) was herein chosen as the reference drug because it is one of the main antifungal drug used. In this context, three different systems of nanoparticles (NPs), Polylactic acid, Poly(lactic-co-glycolic) acid and Alginate, were selected since they present a small particle size (300 to 800 nm), homogenous size distribution, appropriate surface charge, high encapsulation efficiency of Nys (above 70%), prolonged release profile, high adhesion capacity to oral mucosa, permeation capacity through the oral mucosa and safety profile. Also, the NPs successfully maintained the activity of Nys over time. Concerning the stability study the formulations were stable for 6 months. In addition, instead of Nys, extracts from Glycyrrhiza glabra (Licorice) were prepared and their antifungal activity was studied. The results obtained showed that ethanolic extract of Glycyrrhiza glabra L. was the most active extract and that the loaded NPs were successfully produced, presenting a mean size between 100-900 nm and a negative surface charge with high encapsulation efficiency of the extract. In conclusion, this thesis confirmed that all biodhesive nanoformulations using Nys or extracts from plants are viable alternatives for improving drug bioavailability in the oral mucosa. Thus, all nanoformulations might potentially improve the patient compliance due to its extended action and reduced the overall required dosage.
Descrição
Diretores de Tese: Catarina Pinto Reis, Patrícia Mendonça Rijo, Jesús Molpeceres
Palavras-chave
HEALTH SCIENCES, NANOTECHNOLOGY, INFECTIONS, ORAL CAVITY, CANDIDIASIS, PHARMACOLOGY, DOUTORAMENTO EM CIÊNCIAS DA SAÚDE, CIÊNCIAS DA SAÚDE, NANOTECNOLOGIA, INFEÇÕES, CAVIDADE ORAL, CANDIDÍASE, FARMACOLOGIA